The purpose of this research proposal is to investigate whether localized peripheral chronic inflammation contributes to the development of neuroinflammation and ultimately neurodegeneration in vivo. To this end, we will employ somatic mosaic analysis in the Col1-IL1beta-XAT transgenic mouse model recently developed in our laboratory, which utilizes a Cre/loxP based molecular genetic method to temporally and spatially activate a germline-transmitted recombinational substrate containing a dormant IL-1beta transcription unit. Preliminary data demonstrate the development of arthritis in the knees and temporomandibular joints of Col1-IL1beta-XAT transgenic mice after intra-articular Cre administration as assessed by histopathological, immunohistochemical and behavioral studies. Analysis of brain tissue harvested from peripherally-induced Col1-IL1beta-XAT transgenic mice revealed astrocyte and microglia activation by GFAP and MHC class II immunocytochemistry, as well as mRNA upregulation of several inflammation-related genes, including murine IL-1, TNFalpha, MHC-II, GFAP and COX-2. The following specific aims are proposed to further develop and characterize this model. (1) Characterize the development of neuroinflammation following the induction of knee arthritis in young and old Col1-IL1beta-XAT transgenic mice over time. (2) Determine whether peripheral transgene activation impacts brain pathology in compound Col1-IL1beta-XAT/3xTg-AD transgenic mice. These studies will establish whether localized peripheral inflammation and aging are risk factors for the development of neuroinflammation and Alzheimer's disease pathology in mice. Although used here for a pilot investigation of Alzheimer's disease, the Col1-IL1beta-XAT mice can be immediately applied to studies of other chronic neurodegenerative conditions such as ALS, Parkinson's disease, and neurotoxic conditions. Ultimately, this model will contribute to the elucidation of the role of IL-1 in brain inflammation. Such information is critical to our understanding of the benefits of anti-inflammatory therapy in AD and other conditions and will guide the rational application and development of targeted interventions. [unreadable] [unreadable] [unreadable]